Because of changing lifestyle and dietary habits, type 2 diabetes mellitus (DM) is rapidly becoming 1 of the most prevalent diseases in the United States. Current estimates indicate that approximately 15 million have type 2 DM and another 12 million are (undiagnosed) in the early stages. Although renal failure is 1 of the most devastating consequences of type 2 DM, few studies have examined the progression of renal disease and a possible intervention in the early stages. Moreover, the role of transient receptor potential (TRP) cation channels, which are involved in a variety of proliferative diseases, has not been explored in diabetic nephropathy. To study this problem, we developed a high fat mouse model that mimics the condition of human early stage type 2 DM. Using this model, we found mesangial proliferation, collagen IV deposition, basement membrane thickening, glomerular hypertrophy, and albuminuria in the early stages of type 2 DM. However, the HMG-CoA inhibitor and cholesterol-lowering agent, simvastatin (SMV), which increases eNOS by preventing the gerenylation of Rho, reversed these early lesions and significantly reduced the albuminuria. We hypothesize that SMV reverses mesangial expansion by stimulating production of NO, which inhibits TRPC4 (which forms mesangial store-operated Ca2+ channels) via cGMP activated kinase. We will test this hypothesis in 4 Aims: 1. Determine if SMV can reverse the renal lesions associated with mesangial expansion (mesangial proliferation, basement membrane thickening and collagen IV deposition) of a high fat fed mouse model of type 2 DM. 2. Determine^ the role of TRPC4 Ca2+ channels in mesangial proliferation in an in vivo and an in vitro (cultured MC line) model of type 2 DM. 3. Determine whether SMV reverses the mesangial proliferation of type 2 DM via NO-cGMP stimulated inhibition of TRPC4 Ca2+ channels. 4. Determine whether TRPC4 is inactivated via direct phosphorylation by the cGMP-kinase pathway. The preliminary data supporting this hypothesis include: (1) reversal of early stage diabetic nephropathy, including albuminuria, by SMV, (2) in vitro attenuation by TRPC4 antisense of high glucose and high insulin-stimulated mesangial proliferation, (3) an increase in eNOS expression in glomeruli of SMV- treated type 2 DM mice, (4) inhibition of mesangial SOC channels by sodium nitroprusside and 8-Br-cGMP, (5) the identification of PKG-1a in HMC using immunostaining and Western blot and (6) the phosphorylation by 8-Br-cGMP of Ser239-VASP, a specific substrate for PKG-1a in HMC. Lay Summary. Because of dietary habits and lack of exercise, type 2 diabetes mellitus is becoming the biggest health issue in the US. Approximately 30% of type 2 diabetics develop kidney disease causing them to require either dialysis or a kidney transplant. These studies will determine if and how a certain drug, simvastatin, can be used to treat patients in the early stage of type 2 diabetes mellitus and prevent or slow the progression of kidney disease. [unreadable] [unreadable] [unreadable]